This proposal involves the use of autoimmune mouse strains to study the pathogenesis and treatment of lupus. The overall goals of this project are i) to use animal models of SLE to clarify the in vivo mechanisms responsible for autoimmune disease, as well as to understand basis for the efficacy of specific therapeutic interventions in vivo, and ii) to use animal models to develop novel treatment approaches to autoimmune disease and to optimize these approaches as a prelude to clinical trials in humans. The objective of this project is to begin to evaluate the course of autoimmune disease and the response to therapy from the standpoint of antigen-specific T cells. This approach has not previously been available for the study of animal models of lupus and the lack of such a system has been an impediment to the study of fundamental mechanisms of tolerance in vivo. This objective will be met by addressing the following specific aims: Specific Aim I. To define the basis for the efficacy of combined treatment with CTLA41g and CTX in a murine model of SLE This aim is based upon the hypothesis that the beneficial effect we have demonstrated from combining T cell costimulation blockade with cyclophosphamide (CTX) therapy for murine lupus nephritis is the result of complimentary mechanisms of action. To test this hypothesis, we will study the effects of combining CTX with CTLA41g and anti-CD40L in lupus prone mice. We will evaluate the effects of these agents on the function of T and B cells in ex vivo mixed lymphocyte experiments and on nucleosome-specific T cells and the production of nucleosome-specific autoantibodies. We will also evaluate the ability of CTLA41g to significantly extend the efficacy of a short course and/or low doses of CTX for murine lupus Specific Aim II. To examine the effects of CTX and antagonists of costimulation on antiqen-specific T cells. This aim is based upon the premise that progress in translating the fundamental understanding of the induction of tolerance gained from in vitro studies to animal models of autoimmune disease requires the ability to study antigen-specific T cells. We therefore plan to develop class II tetramers loaded with immunodominant nucleosomal autoepitopes that have recently been identified in lupus prone mice and use these tetramers to tract the phenotype, function and response to therapy of autoreactive, antigen-specific T cells in vivo. As an alternate approach to this aim, we will generate ovalbumin TCR transgenic NZB/NZW lupus prone mice in order to evaluate the ability to induce antigen specific tolerance in vivo in an animal model of lupus.